ASXL1 truncating variants in BOS and myeloid leukemia drive shared disruption of Wnt-signaling pathways but have differential isoform usage of RUNX3.

Publisher: BioMed Central Country of Publication: England NLM ID: 101319628 Publication Model: Electronic Cited Medium: Internet ISSN: 1755-8794 (Electronic) Linking ISSN: 17558794 NLM ISO Abbreviation: BMC Med Genomics Subsets: MEDLINE

Original Publication: London : BioMed Central

Repressor Proteins*/genetics ; Repressor Proteins*/metabolism ; Protein Isoforms*/genetics ; Protein Isoforms*/metabolism ; Wnt Signaling Pathway*/genetics; Humans ; DNA Methylation ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/metabolism ; Male ; Female ; Epigenesis, Genetic ; Child ; Adolescent

Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was obtained through the Institutional Ethics Review Boards at UCLA and Hospital for Sick Children. Informed consent was obtained from all research participants according to the protocol approved by the Hospital for Sick Children (REB#1000038847) and UCLA (IRB#11-001087). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
Background: Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML.
Methods: This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions.
Results: Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1.
Conclusion: Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.
(© 2024. The Author(s).)

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T32GM008042 United States GM NIGMS NIH HHS; U01HL153007 United States HL NHLBI NIH HHS; F31HG013462 United States HG NHGRI NIH HHS; MC2015-16 ARRE; IGH-155182 Canada CAPMC CIHR; MOP-126054 CHIR; IDS11-02 Epilepsy Research Program of the Ontario Brain Institute; DP5OD024579 NIH Office of the Director; 20231780 W. M. Keck Foundation

Keywords: ASXL1; Acute myeloid leukemia; Bohring-Opitz syndrome; DNA methylation; Epigenetics; Multi-omics; RNA-sequencing; Transcriptomics

0 (ASXL1 protein, human)
0 (Repressor Proteins)
0 (Protein Isoforms)

Date Created: 20241129 Date Completed: 20241130 Latest Revision: 20241202

20250114

PMC11606099

10.1186/s12920-024-02039-7

39614348